Cathepsin C in health and disease: from structural insights to therapeutic prospects.

Cathepsin C (CTSC) is a lysosomal cysteine protease constitutively expressed at high levels in the lung, kidney, liver, and spleen. It plays a key role in the activation of serine proteases in cytotoxic T cells, natural killer cells (granzymes A and B), mast cells (chymase and tryptase) and neutrophils (cathepsin G, neutrophil elastase, proteinase 3) underscoring its pivotal significance in immune and inflammatory defenses. Here, we comprehensively review the structural attributes, synthesis, and function of CTSC, with a focus on its variants implicated in the etiopathology of several syndromes associated with neutrophil serine proteases, including Papillon-Lefevre syndrome (PLS), Haim-Munk Syndrome (HMS), and aggressive periodontitis (AP). These syndromes are characterized by palmoplantar hyperkeratosis, and early-onset periodontitis (severe gum disease) resulting in premature tooth loss. Due to the critical role played by CTSC in these and several other conditions it is being explored as a potential therapeutic target for autoimmune and inflammatory disorders. The review also discusses in depth the gene variants of CTSC, and in particular their postulated association with chronic obstructive pulmonary disease (COPD), COVID-19, various cancers, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, sudden cardiac death (SCD), atherosclerotic vascular disease, and neuroinflammatory disease. Finally, the therapeutic potential of CTSC across a range of human diseases is discussed.

Self-reported clinical features and treatment effectiveness of Papillon-Lefèvre syndrome patients from five Latin American countries: A cross-sectional online survey study.

BACKGROUND/OBJECTIVES: Most studies about Papillon-Lefèvre syndrome (PLS) are limited to case reports and patients of the same nationality. This study aimed to determine the self-reported prevalence of signs, symptoms and treatment effectiveness in PLS patients from five Latin American countries. METHODS: An online survey was conducted among adult and paediatric patients from Mexico, Argentina, Colombia and Brazil. Data were collected using multiple-choice, open-ended and image-chooser questions on demographics, signs and symptoms, perceived treatment effectiveness and quality of life. RESULTS: Seventeen patients (10 males and 7 females) aged 4-47 years were surveyed. All had palmoplantar hyperkeratosis. Other affected sites were the feet and hand dorsum (82.35%), Achilles tendon (88.24%), forearms (58.82%), legs (29.41%) and glutes (23.53%). They frequently presented hyperhidrosis and nail pitting. Four had a history of delayed umbilical cord separation. All used topical treatments, with moderate effectiveness; half used oral retinoids, perceived as highly effective. Most reported decreased quality of life and walking difficulties. CONCLUSIONS: The study's results align with prior research on PLS, but reveal new insights, including the impact on patients' quality of life and a history of delayed umbilical cord separation. These findings warrant consideration in future research and patient care.

The oral microbiome of a family including Papillon-Lefèvre-syndrome patients and clinically healthy members.

AIMS: The oral microbiota composition of patients diagnosed with Papillon-Lefèvre-syndrome and treated for several years were compared to those existing in the oral cavity of the clinically healthy family members and a cohort of patients having various stages of chronic periodontitis. MATERIALS AND METHODS: A family with two sisters affected with severe periodontitis and with the typical skin symptoms of Papillon-Lefèvre-syndrome, and symptomless parents and third sibling were investigated. The Patients received periodontal treatment for several years and their oral microbiome was analysed by amplicon sequencing. Data were evaluated by microbial cluster analysis. RESULTS: The microbiome of the patients with Papillon-Lefèvre-syndrome was predominated with Aggregatibacter actinomycetemcomitans and associated oral periodontopathogens. Although the clinically healthy family members showed no oral disorder, their microbiome resembled that of subjects having mild periodontitis. CONCLUSIONS: Predominance of A. actinomycetemcomitans in the subgingival microbiome of patients with Papillon-Lefèvre-syndrome suggests that specific treatment strategies directed against this pathobiont may improve the oral health status of the affected individuals. TRIAL REGISTRATION: The study was conducted in accordance with the Declaration of Helsinki and the ethical permission has been issued by the Human Investigation Review Board of the University of Szeged, Albert Szent-Györgyi Clinical Centre (Permission No. 63/2017-SZTE). September 19, 2017.  https://u-szeged.hu/klinikaikutatas/rkeb-altal-jovahagyott/rkeb-2017 .

Survival Rates of Dental Implants in Patients with Papillon-Lefévre Syndrome: A Systematic Review.

AIM: The present review aimed to summarize and evaluate the available literature regarding the survival rate and outcomes of dental implants in patients with Papillon-Lefèvre syndrome (PLS). MATERIALS AND METHODS: An extensive search of the literature was conducted on PubMed, Scopus and Web of Science databases for all data published from January 1996 till April 2020 using a combination of the following keywords: 'Papillon Lefévre Syndrome', 'prosthodontic rehabilitation' and 'dental implant' according to the PRISMA guidelines for the focused research question constructed using the PICO criteria. Clinical trials and observational studies on implant placement in PLS patients reported in English language were included in the study. RESULTS: A total of 10 studies (nine case reports and one case series) comprising 124 dental implants placed in 13 PLS patients were included. The follow-up period ranged from 4 months to 9 years. With regard to implant loading, 9 studies reported delayed loading, while one study did not provide any information regarding the nature of implant loading. The design of prosthodontic superstructure was either a removable or fixed prosthesis. Out of the 124 inserted implants, 20 (16%) were reported as failed. The overall survival rate was 84%. CONCLUSION: The limited available evidence suggests that the survival rate of dental implants in patients with PLS is lower than that among healthy individuals. Nevertheless, no strict contraindication for implant-supported prosthesis seems to be justified in this group of patients. Further longitudinal studies with adequate follow-up periods are highly warranted. CLINICAL SIGNIFICANCE: The prognosis of implant treatment for PLS patients has not yet been established. Dental practitioners should follow a careful approach in planning the dental implant treatment for this cohort of patients.

Palmoplantar keratoderma, oral involvement, and homozygous CTSC mutation in two brothers from Cambodia.

Haim-Munk syndrome (HMS) and Papillon-Lefevre syndrome (PLS) are phenotypic variants of palmoplantar keratoderma (PPK) with progressive early-onset periodontitis and dental caries. HMS and PLS have been associated with homozygous or compound heterozygous mutations in the lysosomal protease gene Cathepsin C (CTSC). There have been only a few documented cases of CTSC mutations in patients from South-East Asia. We report the clinical findings of two Cambodian brothers who presented with diffuse, demarcated PPK with transgrediens extending to the elbows and knees, as well as pachyonychia and dental caries. Arachnodactyly and periodontitis were also found in the older brother. Next-generation sequencing unveiled a homozygous missense variant in CTSC (NM_001814.5: c.1337AC: p.(Asp446Ala)) in both brothers. Both parents were heterozygous for the variant, while an unaffected older brother was homozygous for the wild-type allele. Our study adds to the spectrum of mutations and associated clinical presentations for this rare genodermatosis.

Papillon-Lefèvre syndrome (PLS) with novel compound heterozygous mutation in the exclusion and Peptidase C1A domains of Cathepsin C gene.

Papillon Lefevre syndrome (PLS) manifests with palmoplantar keratoderma, combined with a rapidly progressive periodontitis associated with mutations in Cathepsin C (CTSC) gene. This article reports a 15-year old male proband with typical PLS traits having a novel compound heterozygote with p.Q49X mutation in exon 1 and p.Y259C missense mutation in exon 6 of CTSC gene respectively. The exon 1 mutation, p.Q49X, (found in proband's mother) was located in exclusion domain and exon 6 mutation, p.Y259C (found in proband's father), was present in peptidase C1A, papain C-terminal domain. Interestingly, missense mutation p.Y259C identified in this study was found to be not reported so far. Upon computational analysis, this missense mutation was found to be lethal. Moreover, our protein modelling approach using mutant protein revealed the presence of monomeric structure on contrary to the tetrameric structure of the wild type protein. In addition, in vitro functional characterization of mutant p.Y259C expressed in HEK293 cells showed a significant reduction in CTSC activity (0.015 ± 0.009 mU/ml) when compared with wild type protein (0.21 ± 0.008 mU/ml). Thus, in this study, we have demonstrated that the pathogenic missense mutant p.Y259C might cause PLS by impaired CTSC function.

Papillon-Lefèvre syndrome: Oral aspects and treatment.

Papillon-Lefèvre syndrome (PLS) is a rare disorder characterized by diffuse palmoplantar erythematous, fissured hyperkeratosis, and aggressive periodontal disease that starts in the early periods of childhood. Periodontal disease occurs with the early loss of deciduous teeth at the age of 2 to 4 years, followed by the loss of permanent teeth during adolescence. Prosthodontics management of PLS patients is very complex and sometimes requires invasive therapeutic treatments. Early diagnosis is essential for correct treatment management avoiding the possibility that patients are early edentulous. Management could be a conventional periodontal treatment and pharmacological therapy but in severe cases, digital techniques, could be help the clinician for increased patient comfort and minimized tissue damage.

Diagnosis of Papillon-Lefèvre syndrome: review of the literature and a case report.

Papillon-Lefëvre syndrome (PLS), classified as ectodermal dysplasia, is an autosomal recessive condition related to the cathepsin C (CTSC) gene mutation. The first clinical symptoms, occurring most commonly between the ages of 1 and 4, are palmoplantar hyperkeratosis and also periodontitis resulting in the loss of most or all teeth in the same sequence in which they erupted. Most often the redness of palms and soles precede the occurrence of keratoderma. Moreover, excessive sweating, moderate mental retardation, the tendency to purulent skin and internal organs infection may occur. Lack of cathepsin seems to have a crucial role in the intensity of symptoms. In most of the patients, there can be observed impairment of phagocytosis and chemotaxis of neutrophils, granulocytes, leukocytes and cytotoxic lesion of fibroblasts and macrophages. Also, functional impairment of lymphocytes, neutrophils, and monocytes is observed. The study, using flow cytometry, showed a decreased percentage of T cells CD8+ and increased CD4:CD8 ratio.

Consequences of cathepsin C inactivation for membrane exposure of proteinase 3, the target antigen in autoimmune vasculitis.

Membrane-bound proteinase 3 (PR3m) is the main target antigen of anti-neutrophil cytoplasmic autoantibodies (ANCA) in granulomatosis with polyangiitis, a systemic small-vessel vasculitis. Binding of ANCA to PR3m triggers neutrophil activation with the secretion of enzymatically active PR3 and related neutrophil serine proteases, thereby contributing to vascular damage. PR3 and related proteases are activated from pro-forms by the lysosomal cysteine protease cathepsin C (CatC) during neutrophil maturation. We hypothesized that pharmacological inhibition of CatC provides an effective measure to reduce PR3m and therefore has implications as a novel therapeutic approach in granulomatosis with polyangiitis. We first studied neutrophilic PR3 from 24 patients with Papillon-Lefèvre syndrome (PLS), a genetic form of CatC deficiency. PLS neutrophil lysates showed a largely reduced but still detectable (0.5-4%) PR3 activity when compared with healthy control cells. Despite extremely low levels of cellular PR3, the amount of constitutive PR3m expressed on the surface of quiescent neutrophils and the typical bimodal membrane distribution pattern were similar to what was observed in healthy neutrophils. However, following cell activation, there was no significant increase in the total amount of PR3m on PLS neutrophils, whereas the total amount of PR3m on healthy neutrophils was significantly increased. We then explored the effect of pharmacological CatC inhibition on PR3 stability in normal neutrophils using a potent cell-permeable CatC inhibitor and a CD34+ hematopoietic stem cell model. Human CD34+ hematopoietic stem cells were treated with the inhibitor during neutrophil differentiation over 10 days. We observed strong reductions in PR3m, cellular PR3 protein, and proteolytic PR3 activity, whereas neutrophil differentiation was not compromised.

Clinical and molecular analysis in Papillon-Lefèvre syndrome.

Papillon-Lefèvre syndrome (PLS; MIM#245000) is a rare recessive autosomal disorder characterized by palmar and plantar hyperkeratosis, and aggressively progressing periodontitis leading to premature loss of deciduous and permanent teeth. PLS is caused by loss-of-function mutations in the CTSC gene, which encodes cathepsin C. PLS clinical expressivity is highly variable and no consistent genotype-phenotype correlation has been demonstrated yet. Here we report the clinical and genetic features of five PLS patients presenting a severe periodontal breakdown in primary and permanent dentition, hyperkeratosis over palms and soles, and recurrent sinusitis and/or tonsillitis. Mutation analysis revealed two novel homozygous recessive mutations (c.947T>C and c.1010G>C) and one previous described homozygous recessive mutation (c.901G>A), with parents carrying them in heterozygous, in three families (four patients). The fourth family presented with the CTSC c.628C>T mutation in heterozygous, which was inherited maternally. Patient carrying the CTSC c.628C>T mutation featured classical PLS phenotype, but no PLS clinical characteristics were found in his carrier mother. All mutations were found to affect directly (c.901G>A, c.947T>C, and c.1010G>C) or indirectly (c.628C>T, which induces a premature termination) the heavy chain of the cathepsin C, the region responsible for activation of the lysosomal protease. Together, these findings indicate that both homozygous and heterozygous mutations in the cathepsin C heavy chain domain may lead to classical PLS phenotype, suggesting roles for epistasis or gene-environment interactions on determination of PLS phenotypes.

CTSC compound heterozygous mutations in two Chinese patients with Papillon-Lefèvre syndrome.

OBJECTIVES: To identify the molecular basis of Papillon-Lefèvre syndrome in two Chinese families. METHODS: Peripheral blood and mouth swab samples were obtained, from which genomic DNA and RNA were isolated. Sanger sequencing was employed to identify the mutations. mRNA expression was tested by real-time quantitative PCR. Evolutionary conservation, pathogenicity prediction and impact of protein structures of the mutations were conducted with bioinformatics tools and homology modelling. HEK293 cells were transfected with plasmids expressing wild-type or mutated CTSC. CTSC protein expression level and enzyme activity were explored. RESULTS: Mutation analysis revealed two novel compound heterozygous mutations, the c.190-191insA and c.1211-1212delA in patient 1 and the c.716A>G and c.757+1G>A in patient 2. In both patients, the levels of CTSC mRNA were significantly lower than in their relatives. Homology modelling analysis predicted that the mutations affect the structure and stability of the protein, and in vitro study showed that the CTSC proteins containing the mutations c.190-191insA and c.1211-1212delA, which result in truncated versions of protein, display impaired enzyme activity. The protein containing c.716A>G mutation showed quite similar enzyme activity compared to wild-type CTSC. CONCLUSION: Our data support the molecular mechanism of PLS and enlarge the scope of CTSC gene mutations related to PLS.

Autophagic dysfunction in patients with Papillon-Lefèvre syndrome is restored by recombinant cathepsin C treatment.

BACKGROUND: Cathepsin C (CatC) is a lysosomal enzyme involved in activation of serine proteases from immune and inflammatory cells. Several loss-of-function mutations in the CatC gene have been shown to be the genetic mark of Papillon-Lefèvre syndrome (PLS), a rare autosomal recessive disease characterized by severe early-onset periodontitis, palmoplantar hyperkeratosis, and increased susceptibility to infections. Deficiencies or dysfunction in other cathepsin family proteins, such as cathepsin B or D, have been associated with autophagic and lysosomal disorders. OBJECTIVES: Here we characterized the basis for autophagic dysfunction in patients with PLS by analyzing skin fibroblasts derived from patients with several mutations in the CatC gene and reduced enzymatic activity. METHODS: Skin fibroblasts were isolated from patients with PLS assessed by using genetic analysis. Authophagic flux dysfunction was evaluated by examining accumulation of p62/SQSTM1 and a bafilomycin assay. Ultrastructural analysis further confirmed abnormal accumulation of autophagic vesicles in mutant cells. A recombinant CatC protein was produced by a baculovirus system in insect cell cultures. RESULTS: Mutant fibroblasts from patients with PLS showed alterations in oxidative/antioxidative status, reduced oxygen consumption, and a marked autophagic dysfunction associated with autophagosome accumulation. These alterations were accompanied by lysosomal permeabilization, cathepsin B release, and NLR family pyrin domain containing 3 (NLRP3) inflammasome activation. Treatment of mutant fibroblasts with recombinant CatC improved cell growth and autophagic flux and partially restored lysosomal permeabilization. CONCLUSIONS: Our data provide a novel molecular mechanism underlying PLS. Impaired autophagy caused by insufficient lysosomal function might represent a new therapeutic target for PLS.

Low-dose acitretin in Papillon-Lefèvre syndrome: treatment and 1-year follow-up.

The Papillon-Lefèvre syndrome (PLS) is a rare, autosomal recessive disease that manifests with palmoplantar keratoderma and destructive periodontitis resulting in early onset periodontal breakdown in deciduous and permanent dentition. Management of this condition is difficult. Here we report one 11-year-old consanguineous Muslim boy suffering from PLS. After failing to get any benefit from methotrexate, three cycles of acitretin, each for 2 months, were given 1 month apart. In each cycle, acitretin (25 mg) was given every other day. At the end of the third cycle, treatment was stopped for 4 months to observe the extent of relapse. Thereafter, acitretin (25 mg) was given twice weekly for 4 months and then the patient was followed up for 1 year. Treatment with acitretin resulted in excellent improvement of periodontitis, increase in the alveolar bone height, and periodontal attachment. Improvement remained stable at the end of 1-year follow-up. There was excellent (>75%) improvement in keratoderma at the end of active therapy. Mild worsening of palmoplantar keratoderma was noticed whenever the drug was stopped. It improved when the drug was restarted. Other areas remained stable. At the end of 1-year follow-up, good improvement (50%) in palmoplantar keratoderma was achieved.

Systemic lupus erythematosus complicated with liver cirrhosis in a patient with Papillon-Lefèvre syndrome.

We report the first case of a girl who presented with Papillon-Lefèvre syndrome (PLS) and subsequently developed systemic lupus erythematosus and liver cirrhosis. This indicates that autoimmune diseases can be a complication in patients with PLS. Cathepsin C gene mutations were not found in our patient or her mother. Thus, other genetic factors may have been involved in this patient.

Papillon-Lefèvre syndrome in dental pediatric patient: A comprehensive review.

Introduction: Papillon-Lefèvre syndrome (PLS) is an autosomal recessive genetic disorder characterized by the presence of palmoplantar hyperkeratosis on the hands and feet, as well as severe periodontal disease affecting both the primary and permanent teeth, which can lead to premature tooth loss. Aims: This review aimed to characterize the etiology, clinical manifestations, diagnosis, and recent dental management strategies of pediatric patients with PLS. Material and Methods: A comprehensive search of the electronic literature was conducted using specific keywords such as "Papillon-Lefèvre syndrome in dentistry," "Etiology of Papillon-Lefèvre syndrome," "Oral manifestations of Papillon-Lefèvre syndrome," "Management of Papillon-Lefèvre syndrome," and "Papillon-Lefèvre syndrome." A total of 47 publications that provided relevant information and discussed the various aspects of PLS were identified. Conclusion: The management of PLS necessitates a multidisciplinary approach, including the active involvement of a dental surgeon, dermatologist, and pediatrician to ensure comprehensive care. Extraction of primary teeth and administration of antibiotics is a successful treatment strategy, while placement of removable partial denture is the best option for pediatric patients.

Skeletal indicators of pathology in the context of early tooth loss in children: A systematic literature review.

OBJECTIVE: To provide an evidence-based resource for paleopathologists to consider multiple skeletal indicators of pathology associated with early tooth loss in children to aid in diagnosis. MATERIALS: Three databases (Cochrane Library, MedLine, and Scopus) were used for a review. METHODS: According to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) criteria, a systematic review guideline, 85 articles were selected. RESULTS: A total of 189 children had a syndrome or disease associated with early tooth loss. Our review, based on 25 diseases, lists the bone and dental lesions observable in archeological remains. CONCLUSIONS: Based on a review of the literature, a synthesis of 25 diseases and syndromes that may be associated with premature loss of permanent or deciduous teeth in children was developed for paleopathologists. It highlights the importance of a thorough dental examination by paleopathologists to further assess past health conditions. SIGNIFICANCE: This paper provides an extensive resource addressing early tooth loss in childhood to assist researchers with differential diagnosis. LIMITATIONS: The articles included in this review are case reports based on living populations. SUGGESTIONS FOR FURTHER RESEARCH: Further studies into diseases and their association with early tooth loss would complement this work, as would utilizing the differential diagnoses on archeological individuals to clarify its value and limitations.

Papillon-Lefevre syndrome in twelve Egyptian patients: Five novel CTSC variants and functional characterization of a missense variant and its effect on splicing.

OBJECTIVES: describing the clinical features of twelve Egyptian patients with Papillon-Lefever syndrome (PLS). Five novel mutations in the cathepsin C (CTSC) gene are introduced and the phenotype of the syndrome is expanded by the identification of new clinical features. DESIGN: the clinical, oro-dental data of twelve Egyptian patients from seven unrelated families are described. Sequence analysis of the CTSC gene was performed to identify the causative mutaions. RESULTS: Typical PLS features were presented in all patints but with variable severity. One patient showed atypical dental features including dental structural defect, minimal periodontitis, severe gingivitis, and delayed closure of root apices. Another patient presented with arachnodactyly, dystrophic nails, and buphthalmos in the right eye secondary to uncontrolled congenital glaucoma. Mutational analysis of CTSC gene revealed seven distinct homozygous variants including five novel ones: c.285_286delGT (p.Leu96GlufsTer2), c .302 G>C (p.Trp101Ser), c.622_628delCACAGTC (p.H208Efs*11), c.1331delinsAAAAA (p.G444Efs*4) and c .1343 G>A (p.Cys448Tyr). The previously reported missense variant c .757 G>A (p.Ala253Thr) was found in one patient. This variant is very close to the splice region and by functional studies, we proved that it results in exon skipping and early protein truncation (p.R214Sfs*46). CONCLUSION: We report five novel CTSC variants and describe rare and unusual associated clinical and dental findings such as dental structural defects, delayed closure of root apices, and congenital glaucoma. Therefore, our results expand both the phenotypic and mutational spectrum of PLS.

Long-term results after treatment of periodontitis in patients with Papillon-Lefèvre syndrome: success and failure.

AIM: Retrospective evaluation of periodontal status in patients with Papillon-Lefèvre syndrome (PLS) observed for ≥10 years; identification of factors that may influence treatment outcome; and reporting of the outcome of dental implants in four PLS patients. METHODS: All PLS patients currently registered at the Department of Periodontology, Goethe-University Frankfurt with a follow-up ≥10 years (13-33 years; mean 22 years) were recruited. Eight patients (aged 17-46 years) from five families (three pairs of siblings) were included. RESULTS: After comprehensive periodontal therapy in eight PLS patients, teeth were retained in only two. In six patients, all teeth were extracted, almost entirely due to periodontal reasons. In four patients, teeth were prosthodontically restored with implants. Currently, three patients already show peri-implantitis. CONCLUSIONS: In some PLS patients, periodontitis may be arrested by: combined mechanical and antibiotic periodontal treatment; extraction of severely diseased teeth; oral hygiene instructions; intensive maintenance therapy; and microbiological monitoring and treatment of the infection with Aggregatibacter actinomycetemcomitans. Implants in PLS patients who did not follow any maintenance programme have a high risk of peri-implantitis and implant loss. Treatment of PLS patients has always to be considered as high-risk cases.

Diagnosis and Management of Papillon-Lefevre Syndrome: A Rare Case Report and a Brief Review of Literature.

Papillon-Lefevre syndrome (PLS) manifests as an autosomal recessive disorder caused by a mutation in the cathepsin C (CTSC) gene. This genetic alteration results in palmoplantar hyperkeratosis, rapid onset of periodontitis, and premature shedding of both primary and permanent teeth. The major etiological factor responsible for the development of this disorder appears to be variations in the CTSC gene, which is responsible for the production of the cathepsin C enzyme in the body. The multifactorial aetiology of the syndrome is influenced by immunologic, genetic, or microbial factors. This case report presents a clinical picture of a 21-year-old Indian male patient with oligodontia and mobile teeth accompanied by palmoplantar keratosis and a history of recurrent infection. The detailed family history of the patient revealed genetic relevance with PLS. This article will discuss in detail the diagnosis, evaluation and treatment modalities involved in the management of the case.